Repetitive Transcranial Magnetic Stimulation Combined With Median Nerve Electrical Stimulation for Severe Traumatic...

Severe traumatic brain injury (sTBI) often leads to prolonged coma and poor neurological outcomes. Noninvasive neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and median nerve electrical stimulation (MNS) have shown potential in promoting arousal. However, the efficacy of combining these two approaches remains unclear.

In this randomized controlled trial, 86 patients with sTBI-induced coma were assigned to rTMS (n = 29), MNS (n = 29), or combination therapy (n = 28) for 4 weeks. Outcomes included awakening efficacy, EEG grading, cerebral blood-flow parameters (Vm, Vd, Vs, pulsatility index [PI]), GCS, and MoCA. Safety events were recorded.

At week 4, the combination group demonstrated significantly higher overall awakening efficacy (92.86%, 26/28) compared with the rTMS (65.52%, 19/29) and MNS (62.07%, 18/29) groups (p < 0.05; number needed to treat [NNT] ≈ 4 for combination vs. MNS). GCS scores improved significantly within all groups (all p < 0.05), with the greatest mean change observed in the combination group (baseline 5.19 ± 0.62 → week 4: 11.23 ± 1.12; Δ+6.04), followed by MNS (Δ+4.50) and rTMS (Δ+4.19); between-group differences favored combination therapy (p < 0.05). EEG grading shifted toward lower-severity categories in all groups, with the combination group achieving the highest proportion of Grade I-II normalization at week 4 (71.4%, 20/28) compared with rTMS (62.1%, 18/29) and MNS (37.9%, 11/29). Transcranial Doppler-derived cerebral blood-flow velocities (Vm, Vs, Vd) increased and the pulsatility index decreased across all groups, with the combination group demonstrating the most pronounced hemodynamic improvement relative to either monotherapy (all p < 0.05). In an exploratory analysis restricted to patients who regained sufficient responsiveness to undergo cognitive testing (combination: 26/28 [92.9%]; rTMS: 19/29 [65.5%]; MNS: 18/29 [62.1%]), MoCA scores at week 4 indicated mild-to-moderate cognitive impairment across all groups (combination: 21.35 ± 2.87; rTMS: 18.74 ± 3.26; MNS: 18.22 ± 3.41), with numerically highest scores in the combination group; however, given the differential testability rates-which corresponded directly to awakening status-these findings are subject to inherent selection bias and should be interpreted as hypothesis-generating only. No seizures were observed throughout the study period. Adverse events were infrequent and did not differ significantly among groups (combination: 10.7%; rTMS: 20.7%; MNS: 27.6%; all pairwise p > 0.05), with rates numerically lowest in the combination group.

In patients with severe traumatic brain injury and persistent coma, rTMS combined with right MNS significantly improves awakening efficacy, neurophysiological indicators (EEG grading), and cerebral hemodynamics compared with either modality alone. GCS improvement was greatest with combination therapy. Exploratory cognitive findings (MoCA in testable subsets) suggest potential additional benefits, though these require confirmation in future trials employing outcome instruments applicable to all randomized patients. Adverse event rates were low across all groups, with no seizures observed; the study was not powered for formal safety comparisons. These findings support the dual-pathway neuromodulation paradigm as a promising strategy for consciousness recovery in sTBI and warrant confirmation in multicenter, sham-controlled trials with extended follow-up.